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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Identification and functional annotation of genome-wide ER-regulated genes in breast cancer based on ChIP-Seq data
Min Ding1, Haiyun Wang, Jiajia Chen
1Department of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
Abstract:
Estrogen receptor (ER) is a crucial molecule symbol of breast cancer. Molecular interactions between ER complexes and DNA regulate the expression of genes responsible for cancer cell phenotypes. However, the positions and mechanisms of the ER binding with downstream gene targets are far from being fully understood. ChIP-Seq is an important assay for the genome-wide study of protein-DNA interactions. In this paper, we explored the genome-wide chromatin localization of ER-DNA binding regions by analyzing ChIP-Seq data from MCF-7 breast cancer cell line. By integrating three peak detection algorithms and two datasets, we localized 933 ER binding sites, 92% among which were located far away from promoters, suggesting long-range control by ER. Moreover, 489 genes in the vicinity of ER binding sites were identified as estrogen response elements by comparison with expression data. In addition, 836 single nucleotide polymorphisms (SNPs) in or near 157 ER-regulated genes were found in the vicinity of ER binding sites. Furthermore, we annotated the function of the nearest-neighbor genes of these binding sites using Gene Ontology (GO), KEGG, and GeneGo pathway databases. The results revealed novel ER-regulated genes pathways for further experimental validation. ER was found to affect every developed stage of breast cancer by regulating genes related to the development, progression, and metastasis. This study provides a deeper understanding of the regulatory mechanisms of ER and its associated genes.
Insights
This study reveals estrogen receptor (ER) binding sites in breast cancer cells, showing most are distant from gene promoters and regulate crucial cancer-related genes, offering new therapeutic targets.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Estrogen receptor (ER) plays a key role in breast cancer, regulating gene expression. The precise locations and mechanisms of ER-DNA interactions remain largely unknown.
- Understanding ER binding is crucial for deciphering breast cancer development and identifying therapeutic targets.
Purpose of the Study:
- To map genome-wide estrogen receptor (ER) binding sites in breast cancer cells.
- To identify genes regulated by ER and understand the functional pathways involved.
- To investigate the relationship between ER binding sites, genetic variations, and estrogen-regulated genes.
Main Methods:
- Analysis of ChIP-Seq data from MCF-7 breast cancer cells using integrated peak detection algorithms.
- Comparison with gene expression data to identify estrogen response elements.
- Annotation of nearby genes using Gene Ontology (GO), KEGG, and GeneGo pathway databases.
Main Results:
- 933 ER binding sites were identified, with 92% located far from gene promoters, indicating long-range regulatory mechanisms.
- 489 estrogen-regulated genes were identified near ER binding sites.
- 836 single nucleotide polymorphisms (SNPs) were found near ER binding sites within 157 ER-regulated genes.
- Novel ER-regulated pathways involved in breast cancer development, progression, and metastasis were revealed.
Conclusions:
- Estrogen receptor (ER) primarily exerts long-range control over gene expression in breast cancer cells.
- This study provides a comprehensive map of ER binding sites and identifies novel ER-regulated genes and pathways.
- The findings enhance our understanding of ER's role in all stages of breast cancer, paving the way for new therapeutic strategies.
